Cannabis remains the most commonly used illicit drug worldwide, including the United States. Not only does a relatively large percentage of the population report using cannabis, but like other drugs of abuse, a significant proportion of those persons use it habitually and meet diagnostic criteria for drug-use disorders. Moreover, cannabis-use disorders are associated with treatment admission and relapse rates comparable to other drugs of abuse perceived as more harmful. Despite the significant public health concern posed by cannabis use, there has been limited preclinical or clinical research that has focused explicitly on the identification and development of medications to treat cannabis-use disorders. Data from preclinical and clinical research suggest that agonist replacement treatment is an effective means to manage drug-use disorders, and that this strategy would be viable for cannabis-use disorders as well. The experiments proposed here represent the initial step of evaluating GABAergic drugs as potential "agonist-like" pharmacotherapies for cannabis-use disorders. GABA is being targeted because there is substantial overlap in the effects produced by cannabinoids and drugs acting at central GABAergic systems, and neuroanatomical, neurochemical and behavioral studies support a functional link between cannabinoid and GABAergic systems. The studies proposed here will test the ability of the selective GABA reuptake inhibitor tiagabine, the GABAA positive modulator diazepam and the GABAB agonist baclofen to enhance the behavioral and physiological effects of ?9-THC, thus examining the "agonist-like" profile of GABAergic drugs with varying mechanisms of action. The primary outcome for these experiments is the interoceptive cue produced by ?9-THC. The interoceptive effects of ?9-THC will be measured using the drug-discrimination procedure, which is a pharmacologically specific and sensitive means to characterize drugs and drug interactions. In addition, subjective effects questionnaires, psychomotor performance and memory tasks, and cardiovascular and thermal measures of physiology will be included to more fully assess the effects of ?9-THC alone and in combination with GABAergic compounds. The experiments proposed here are novel and innovative because there are very few studies in humans to have tested the effects of GABAergic drugs on cannabinoids. In addition, these studies are important for at least three reasons. First, and perhaps most importantly, the data generated from the proposed experiments will provide the direction and foundation for future studies aimed at the development of GABAergic treatments for cannabis-use disorders. Second, these data will provide valuable information regarding the neurobiology of the effects of cannabinoids in humans by examining the interactions between cannabinoid and GABAergic systems. Finally, these experiments will provide translational information regarding the extent to which the results from preclinical studies that have evaluated CB-GABA interactions generalize to humans. Public Health Relevance: Cannabis is the most commonly used illicit drug in the United States and its use is associated with rates of development of abuse and dependence, treatment admission and relapse that are comparable to other illicit drugs that are misperceived as more harmful. Currently there is no effective pharmacological treatment for cannabis-use disorders. The experiments proposed here represent the initial step of evaluating GABAergic drugs as potential pharmacotherapies by characterizing interactions between ?9-THC and the selective GABA reuptake inhibitor tiagabine, the GABAA positive modulator diazepam and the GABAB agonist baclofen.